BACKGROUNDAdult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders. METHODSWe analyzed peripheral-blood exome sequence data independent of clinical phenotype and inheritance pattern to identify deleterious mutations in ubiquitin-related genes. Sanger sequencing, immunoblotting, immunohistochemical testing, flow cytometry, and transcriptome and cytokine profiling were performed. CRISPR-Cas9edited zebrafish were used as an in vivo model to assess gene function. RESULTSWe identified 25 men with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. (The gene UBA1 lies on the X chromosome.) In such patients, an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopenias, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis. Most of these 25 patients met clinical criteria for an inflammatory syndrome (relapsing polychondritis, Sweet's syndrome, polyarteritis nodosa, or giant-cell arteritis) or a hematologic condition (myelodysplastic syndrome or multiple myeloma) or both. Mutations were found in more than half the hematopoietic stem cells, including peripheral-blood myeloid cells but not lymphocytes or fibroblasts. Mutations affecting p.Met41 resulted in loss of the canonical cytoplasmic isoform of UBA1 and in expression of a novel, catalytically impaired isoform initiated at p.Met67. Mutant peripheral-blood cells showed decreased ubiquitylation and activated innate immune pathways. Knockout of the cytoplasmic UBA1 isoform homologue in zebrafish caused systemic inflammation. CONCLUSIONSUsing a genotype-driven approach, we identified a disorder that connects seemingly unrelated adult-onset inflammatory syndromes. We named this disorder the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome.

Objective Somatic mutations in UBA1 cause a newly defined syndrome known as VEXAS (vacuoles, E1 enzyme, X‐linked, autoinflammatory, somatic syndrome). More than 50% of patients currently identified as having VEXAS met diagnostic criteria for relapsing polychondritis (RP), but clinical features that characterize VEXAS within a cohort of patients with RP have not been defined. We undertook this study to define the prevalence of somatic mutations in UBA1 in patients with RP and to create an algorithm to identify patients with genetically confirmed VEXAS among those with RP. Methods Exome and targeted sequencing of UBA1 was performed in a prospective observational cohort of patients with RP. Clinical and immunologic characteristics of patients with RP were compared based on the presence or absence of UBA1 mutations. The random forest method was used to derive a clinical algorithm to identify patients with UBA1 mutations. Results Seven of 92 patients with RP (7.6%) had UBA1 mutations (referred to here as VEXAS‐RP). Patients with VEXAS‐RP were all male, were on average ≥45 years of age at disease onset, and commonly had fever, ear chondritis, skin involvement, deep vein thrombosis, and pulmonary infiltrates. No patient with VEXAS‐RP had chondritis of the airways or costochondritis. Mortality was greater in VEXAS‐RP than in RP (23% versus 4%; P = 0.029). Elevated acute‐phase reactants and hematologic abnormalities (e.g., macrocytic anemia, thrombocytopenia, lymphopenia, multiple myeloma, myelodysplastic syndrome) were prevalent in VEXAS‐RP. A decision tree algorithm based on male sex, a mean corpuscular volume >100 fl, and a platelet count <200 ×103/μl differentiated VEXAS‐RP from RP with 100% sensitivity and 96% specificity. Conclusion Mutations in UBA1 were causal for disease in a subset of patients with RP. This subset of patients was defined by disease onset in the fifth decade of life or later, male sex, ear/nose chondritis, and hematologic abnormalities. Early identification is important in VEXAS given the associated high mortality rate.

Introduction Knee osteoarthritis (OA) is characterized by pain and functional deficits. Common conservative strategies include medications, physical therapy, and intra‐articular injections. Recently, treatment using autologous cell injections has increased. Objective To characterize the cellular content of bone marrow aspirate (BMA) and to evaluate the effect of intra‐articular autologous BMA injections in patients with mild knee OA. Design Prospective pilot observational study. Setting Academic institution. Patients Eleven patients with unilateral or bilateral mild knee OA (15 knees) were included in the cellular analysis. Ten patients (13 knees) were included in the overall (cellular and clinical) analysis. Interventions BMA was aspirated from patients’ iliac crests and then injected intra‐articularly under fluoroscopic and/or ultrasound guidance. BMA samples were analyzed using flow cytometry, colony forming unit (CFU) assays, and enzyme‐linked immunosorbent assays. Questionnaires assessing pain and function were administered preinjection and at 1, 3, 6, and 12 months postinjection. Side effects and satisfaction were assessed. Main Outcome Measures Total nucleated cell (TNC) concentration, mesenchymal stem cell (MSC) concentration, CFU count, and interleukin‐1 receptor antagonist (IL‐1Ra) concentration. Results BMA sample analyses revealed wide ranges in TNC concentration (173300‐4 491 050 cells/mL), MSC concentration (0‐500 cells/mL), CFUs (0‐19), and IL‐1Ra concentration (2806‐29 394 pg/mL). Improvements in Knee Injury and Osteoarthritis Outcomes Score for Joint Replacement were observed throughout the 12‐month follow‐up period (F[4,12] = 12.29, P < .001). Additionally, current, usual, best, and worst numerical rating scale pain scores significantly decreased over time (P < .001). Patient satisfaction was high (range: 8.1 ± 2.1‐8.8 ± 1.9), and side effects were uncommon. Conclusions The cellular content of BMA samples varied widely between patients and was lower than the anticipated yield reported by the device's manufacturer. However, intra‐articular BMA injections for knee OA in a small pilot cohort appeared to be safe with potential therapeutic value. Larger, prospective, double‐blinded studies are warranted.

No abstract